It is known that elevated levels of serum cholesterol may lead to atherosclerosis and coronary heart disease. Therefore compounds which inhibit the biosynthesis of cholesterol and thereby effect serum cholesterol levels are of interest.
Lanosterol is an intermediate in the biosynthesis of cholesterol, requiring, among other transformations, enzymatic removal of the methyl group at carbon 14. The removal of the methyl group from carbon 14 is effected by the enzyme lanosterol 14.alpha.-methyl demethylase. Oxidative removal of the C-14 methyl group by the cytochrome P-450 dependent lanosterol 14.alpha.-methyl demethylase produces 30-oxygenated steroids (14-CH.sub.2 OH and 14-CHO) as intermediates. These oxygenated intermediates are proposed to play a role as regulatory steroids in the control of the overall biosynthetic pathway of cholesterol. The activity of 3-hydroxy-3-methylglutaryl coenzyme A reductase (HMG-CoA reductase), which is a rate-limiting enzyme in cholesterol biosynthesis, is also proposed to be influenced by changes in the concentration of oxygenated intermediates in the reaction of lanosterol 14.alpha.-methyl demethylase. Relevant references are Havel et al, J. Biol. Chem., 254:9573 (1979), Gibbons et al, J. Biol. Chem., 255:395 (1980).
The ability of certain naturally occurring and synthetic oxysterols to suppress the activity of HMG-CoA reductase in whole cells has been demonstrated. Gibbons, Biochemical Society Transactions, 11:649 (1983); Parish et al, Lipids, 21:26 (1986); Trzaskos et al, J. Biol. Chem., 261:16937 (1986).
Recognition of the importance of reducing cholesterol biosynthesis has stimulated efforts to synthesize inhibitors of lanosterol 14.alpha.-methyl demethylase as well as oxysterol regulators of HMG-CoA reductase activity.
European Patent Application 276,823 (Aug. 3, 1988) disclosed the use of 14,15-substituted lanosterol including 14-carboxy sterols, as hypocholesterolemic agents. The substituted lanosterols are described as active in inhibiting lanosterol 14.alpha.-methyl demethylase activity and suppressing HMG-CoA activity.
In U.S. Pat. No. 4,202,891, Schroepfer et al disclosed 15-oxygenated sterols as inhibitors of mevalonic acid formation, mevalonic acid being an intermediate in the biosynthesis of cholesterol.
Parish et al, in Lipids, 21:27 (1986) "Oxysterols: Chemical Synthesis, Biosynthesis and Biological Activities" report on the inhibition of HMG-CoA reductase activity by 9.alpha.,11.alpha.-epoxycholest-7-en-3.beta.-ol, 3.beta.-hydroxycholest-8-en-7-one and 3.beta.-hydroxycholest-8-en-11-one. Parish et al also note that 14.alpha.-hydroxymethyl derivatives of 24,25-dihydrolanosterol have been reported as potent inhibitors of HMG-CoA reductase activity in whole cells.
Shafiee et al, J. Lipid Res., 27:1, (1986) reported on 14-aldehyde sterols.
Cheng et al, J. Chem. Soc. Perkin. Trans. I., 2403 (1988) reported the isolation of a 14-carboxy sterol (penasterol) from a marine sponge.